Inflammatory bowel disease (IBD) is a disease marked by ongoing mucosal injury and regeneration. We have applied mRNA transcript profiling by GeneChip hybridization and high-throughput library sequencing to identify novel or unsuspected genes in the gastrointestinal mucosa that potentially mediate protective or regenerative programs. Our results have identified members of the REG gene family as among the most highly induced mRNAs in IBD mucosa, suggesting that they may serve an important role in mucosal repair. While the biological function for this gene family remains poorly understood, recent work has suggested that REG proteins may serve as tissue mitogens. We have identified and purified a novel REG cell surface receptor (REG-R) that binds to Reg I-alpha. Treatment with recombinant Reg I-alpha resulted in rapid and dose-dependent activation of the ERK MAP kinase pathway. The REG-R receptor is a transmembrane protein that contains only a small cytoplasmic domain and lacks structural features required for receptor coupling to downstream signaling pathways. Accordingly, we have also identified a second protein that co-purifies with REG-R. Our three part hypothesis is: (1) all members of the REG gene family bind and activate this cell surface receptor, (2) the active receptor complex contains the REG-R and an additional subunit possessing the cytoplasmic determinants required for signal transduction, and (3) individual REG proteins and their cognate receptor complex constitute a new receptor-ligand system with unique importance to the maintenance and repair of the gastrointestinal mucosa. We propose to use newly developed tools to directly test this hypothesis in three specific aims: (1) determine if differences exist between individual REG genes in their ability to bind and activate receptor-mediated signal transduction. Characterize the spatial relationship between mucosal populations expressing the REG-R and the location of REG gene products in normal and diseased gastrointestinal mucosa; (2) Characterize additional components of the REG-R complex and elucidate the structural requirements of ligand-mediated receptor signaling; and (3) Investigate the role for the REG-R-ligand system in vitro and in vivo as a prelude to developing a murine REG-R loss-of-function model. This includes experiments to examine the functional role served by this receptor ligand system in vitro and under in vivo pathologic models associated with ectopic or increased expression of REG proteins. These studies will provide important new insights into factors that regulate mucosal regenerative programs and may lead to new ways to treat diseases affecting the gastrointestinal mucosa like inflammatory bowel disease.